Jerusalem researchers discover how cancerous tumors become resistant to drugs

By JUDY SIEGEL-ITZKOVICH04/10/2014

Breakthrough is crucial to enabling the rapidly developing field of “personalized medicine” in cancer treatment.

In what has been called a breakthrough discovery, Hebrew University Medical Faculty researchers have identified a process in which cancer cells become resistant to certain drugs, a process that they say will lead to a reliable prediction as to which patients will be helped by chemotherapy and recover and which the drugs will not help.

These finding – recently submitted as patent applications by Yissum, HU’s technology transfer company – could enable the reversal of the process and inhibit metastasis of malignant tumor cells.

Cancer has become the No. 1 killer in Israel and much of the Western world, surpassing cardiovascular disease.

While many types of chemotherapy have been developed against cancer, oncologists don’t know before starting treatment whether a patient might benefit from a particular drug. So being able to identify through a lab test whether a patient’s tumor is either resistant or sensitive to a specific drug is crucial to enabling the rapidly developing field of “personalized medicine.”

The study by HU graduate student Avi Maimon under the supervision of Dr. Rotem Karni of the medical faculty’s Institute for Medical Research Israel-Canada was published Thursday evening in the journal Cell Reports.

Maimon and Karni found that breast, lung and colon cancer cells change the structure of an enzyme called Mnk2, which is involved in the transmission of information from the environment/ body into the cell.

The researchers showed that the enzyme has two forms – a “normal” one that inhibits cancer and another form that promotes cancer development.

Karni’s team further showed that cancer cells change the structure of the Mnk2, so they eliminate the form that inhibits cancer and elevate the form that induces it, thus allowing the cancer cells to survive and grow faster. In addition, the researchers found that the anti-cancer form of the enzyme activates a program of apoptosis (suicide) in normal cells under stress conditions.

To fight this process, Karni and his colleagues developed molecules that can convert the cancerous form of the Mnk2 enzyme back into its normal form so they become sensitive to stress and to absorbing chemotherapy drugs.

More importantly, the molecules that change the cancerous form of Mnk2 into the normal form will make it possible to overcome the drug resistance of cancer cells, making them instead sensitive and responsive to various anti-cancer treatments. Further laboratory work on this aspect is continuing.

“The mechanism we discovered explains how cancer cells eliminate the anti-cancer form of Mnk2 without changing their DNA and how they become resistant to anti-cancer treatments – a problem that exists for almost every cancer treatment today,” said Karni. “The new molecules we developed to change the structure of the Mnk2 enzyme back to its normal form will enable re-sensitizing cancer cells into anti-cancer therapies,” he added.

This research could lead to development of a new biomarker for testing the sensitivity of a patient to specific drugs, Karni suggested. The possibility of examining whether a patient will benefit from a specific drug treatment before the treatment starts is of primary medical interest. His research group is now developing a diagnostic test for the marker it found.